This grant will be performed primarily in Argentina at the Department of Physiology, School of Medicine, University of Buenos Aires in collaboration with Mario Rafael Pagani (email: pagani@fmed.uba.ar;phone and fax: 54-(11)-5950-9500 x 2159), as an extension of NIH Grant No. (5R01HL071207-08), 08/01/2002 to 01/31/2013. The long-term goal of our research is to treat intellectual disability and restore normal learning and behavior. The aim of this research project is to advance our understanding of the molecular basis of the intellectual disability in Noonan syndrome (NS). NS is a genetic disorder caused by gain-of-function mutations in nine genes encoding components of the Ras/MAPK signaling pathway (i.e., CBL, SHP2, SOS, RAS, RAF and MEK proteins). In addition to morphological abnormalities such as cardiac defects, intellectual disability is a common feature in NS and related disorders, also caused by mutations in genes encoding proteins in the Ras/MAPK pathway, documenting that enhancement of RAS signaling produces neurocognitive defects. By using transgenic Drosophila melanogaster lines with NS gain-of-function mutations in the fly PTPN11 orthologue, corkscrew (csw), we identified genes that strongly control developmental defects including Ras/MAPK pathway regulators but also ones encoding proteins of the Notch and JAK/STAT pathway. In addition, we recently showed that different csw gain-of-function alleles impair a fundamental property of learning called the spacing effect, which refers to a longer-lasting memory when study session is spaced over time. Of note, the spacing effect and memory deficit was "curable" by a pharmacological or behavioral approach. In this research project we will examine the role of RAS, Notch and JAK/STAT pathways in the spacing effect and the signaling mechanisms involved by using a Drosophila model system. Taken as a whole, the studies proposed in this application will delineate the range of genes that cause NS when mutated as well as provide insights into the effects of their mutant protein products at the biochemical, cellular, and organismal levels. The insights gained will be leveraged in the future to elucidate genetic causes of cognitive defects as wel as to develop novel therapeutic strategies to ameliorate these phenotypes. PUBLIC HEALTH RELEVANCE: A better understanding the molecular mechanisms underlying intellectual disability in Noonan syndrome and related disorders will lead to potential pharmacological or behavioral therapies. Our current understanding about Noonan syndrome and related disorders is limited to mechanisms related with the alteration of Ras/MAPK signaling pathway and only a few mechanisms about the principal genes involved are known for intellectual disability. Characterizing the role of other genes associated with Noonan syndrome alteration, RAS, Notch and STAT, will provide additional targets for scientific studies as wel as for therapeutic intervention.